1. Field of the Invention
The present invention relates to a transdermal therapeutic system (TTS) for the transcutaneous administration of tolterodine over several days, and to methods of producing said TTS.
2. Description of Related Art
The bioavailability of active ingredients which are administered orally is often unsatisfactory. The intravenous administration of active ingredients is frequently unpleasant and unsatisfactory for patients. In the bile duct, the hepatic metabolisation of many active ingredients can result in undesirable concentration ratios, toxic by-products and in a reduction of efficacy, or even in a loss of efficacy. Compared with oral administration, transdermal administration of active ingredients has various advantages. The supply of active ingredient can be better controlled over a longer period, whereby high blood level fluctuations are avoided. Moreover, the requisite therapeutically effective dose can usually be considerably reduced. Furthermore, patients often prefer a patch to pills which have to be taken once or many times a day.
In the past, there has been a multiplicity of transdermal therapeutic systems (TTS) of different structures which have been proposed for different active ingredients in order to overcome the aforementioned disadvantages of the non-transdermal administration of active ingredients.
Thus the technical documents listed below describe systems for the parenteral administration of a broad multiplicity of active ingredients which react systemically or locally; these systems are based either on a controlled dose or on the overall release of active ingredient.
Examples thereof include U.S. Pat. Nos. 3,598,122A; 3,598,123A, 3,731,683A, 3,797,494A; 4,031,894A; 4,201,211 A; 4,286,592 A; 4,314,557 A; 4,379,454 A: 4,435,180 A; 4,559,222 A; 4,568,343 A; 4,573,995 A, 4,588,580 A; 4,645,502 A; 4,702,282 A; 4,788,062 A; 4,816,258 A; 4,849,226 A; 4,908,027 A: 4,943,435 A and 5,004,610 A.
In the late sixties of this century, however, it was initially assumed, based on theoretical considerations, that any active ingredient exhibiting a short half-life, high efficacy and good permeation through the skin was suitable for reliable and effective administration by means of a TTS. However, it was not possible to realise these initial expectations regarding the possibility of the transdermal administration of active ingredients by means of a TTS. The reason for this is mainly that skin has been provided by nature with a variety of insuperable qualities in order to maintain its function as an intact barrier to the ingress of extraneous substances into the body (in this respect, see: Transdermal Drug Delivery: Problems and Possibilities, B. M. Knepp et al., CRC Critical Review and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987)).
Therefore, transdermal administration is available only for those few active ingredients which comprise a suitable combination of many favourable characteristics. The requisite characteristics, which ensure reliable and effective transdermal administration, cannot be predicted for a given substance, however.
The requirements imposed on an active ingredient which is suitable for transdermal administration are:
capable of passing through the skin,
no impairment of the adhesive capacity of the patch by the active ingredient,
avoidance of skin irritation,
avoidance of allergic reactions,
favourable pharmacokinetic properties,
favourable pharmacodynamic properties,
a relatively wide therapeutic window,
metabolic properties which are consistent with therapeutic use comprising continuous delivery.
The above list of requirements is undoubtedly not exhaustive. So that an active ingredient can be available for transdermal administration, the xe2x80x9ccorrectxe2x80x9d combination all of these requirements is desirable.
The aforementioned requirements for the active ingredient apply similarly to the TTS composition which contains the respective active ingredient and the nature of the structure thereof.
Transdermal therapeutic systems (TTS) are usually patches which are provided with an impermeable outer layer, a peelable protective layer and a matrix which contains an active ingredient, or a reservoir which contains an active ingredient and comprises a semipermeable membrane. In the first case these are termed matrix patches, and in the second case they are termed membrane systems.
The substances used for the outer layer are usually polyesters, polypropylene, polyethylene, polyurethane etc., which can also be metallised or pigmented. Suitable substances for the peelable protective layer include polyesters, polypropylene and also paper with a silicone and/or polyethylene coating. Fluoropolymers are also used.
A multiplicity of substances, such as those based on polyacrylate, silicones, polyisobutylene, butyl rubber, styrene/butadiene copolymers or styrene/isoprene copolymers, can be used as the matrix which contains the active ingredient.
The membranes which are used in membrane systems can be microporous or semipermeable, and are usually based on an inert polymer, particularly polypropylene, polyvinyl acetate or silicones.
Whereas matrix compositions which contain an active ingredient can be self-adhesive, matrix compositions which contain an active ingredient but which are not self-adhesive can also be used depending on the active ingredient used, but the structure of the patch or TTS consequently has to be provided with an overtape.
To ensure the requisite flux of active ingredient, skin penetration enhancers are frequently necessary as additives, such as aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols, each of which is monohydric or polyhydric and contains up to 8 C atoms, alcohol/water mixtures, saturated and/or unsaturated fatty alcohols which each contain 8 to 18 carbon atoms, saturated and/or unsaturated fatty acids which each contain 8 to 18 carbon atoms and/or esters thereof, as well as vitamins.
Moreover, stabilisers such as polyvinyl pyrrolidone, xcex1-tocopherol succinate, propyl gallate, methionine, cysteine and/or cysteine hydrochloride are frequently added to the matrix which contains the active ingredient.
As shown by the above statements, numerous TTS structures and materials which are used therefor are known. However many interacting requirements have to be taken into account if a drug in form of a TTS is to satisfy a medical need.
The following problems have to be taken into account during the development of a TTS containing an active ingredient:
1. The permeability of the skin to the active ingredient may be too low to achieve the therapeutically necessary rate of penetration, and/or the delay time (xe2x80x9clag-timexe2x80x9d) until the therapeutically necessary plasma level is reached is too long, with the consequence that additives which increase the rate of penetration through the skin have to be administered.
2. The polymer matrix which contains the active ingredient, and which optionally contains skin penetration enhancers in addition, may not be physically stable over an extended period of storage. In particular, recrystallisation of the active ingredient may occur, which results in an uncontrollable decrease in the capacity of the TTS to release active ingredient.
3. For self-adhesive polymer films, a high content of active ingredient and/or of skin penetration enhancers in the polymeric backing material makes it difficult to achieve the optimum adhesive properties for the transdermal system.
4. For applications comprising several days of administration, the rate of resorption of the active ingredient decreases in an unacceptable manner, so that additional control layers and/or control components are necessary.
5. Furthermore, it is known from the literature that the fatty acid esters of polyhydric alcohols which are frequently used to promote penetration through the skin contain impure blending agents of variable quality. This results in increases in penetration which exhibit poor reproducibility (Burkoth et al. 1996, DE 196 22 902 A1).
The problems described above have therefore given rise to a multiplicity of designs of transdermal therapeutic systems, which are reflected in the prior art in this field.
DE 196 53 606 A1 describes an adhesive and bonding agent for a TTS comprising defined quantitative proportions of the components a), a (meth)acrylate polymer which may contain quaternary ammonium groups, b) an organic di- or tricarboxylic acid, and c), a plasticiser, which can be a triester of citric acid.
As shown by the above statements, many patch structures are known, as are the materials used therefor. Nevertheless, for many active ingredients which are processed to form transdermal therapeutic systems there has hitherto been a considerable need for TTS systems which facilitate the release of active ingredient as required by the therapy concerned without involving costly structures, and which comprise the optimum relationships with regard to their constituents overall. This also applies to the active ingredient tolterodine if this is to be administered transcutaneously.
Tolterodine is the international non-proprietary name (INN) for the R-isomer of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (IUPAC description: (+)-(R)-2-(xcex1[2-(diisopropylamino)ethyl]benzyl)4-methylphenol)). The term xe2x80x9ctolterodinexe2x80x9d is employed hereinafter to mean N,N-diisopropyl-3-(2-hydroxy-5-ethylphenyl)-3-phenylpropylamine. Inasmuch as reference is made to the individual isomers, namely the R- or S-isomer or a racernic mixture of the R- and S-isomers, these are referred to as R-, S- and R,S-tolterodine, respectively.
Tolterodine is used therapeutically for the treatment of bladder instability associated with the symptoms of involuntary discharge of urine, pollakiuria and urinary incontinence. The recommended dose is 2 mg of tolterodine twice daily, and is administered orally.
After oral application, tolterodine is metabolised to very different degrees in the bile duct. Thus the absolute bioavailability of tolterodine is 65% for slow metabolisers, but is only 17% for rapid metabolisers. Since even the resulting 5-hydroxymethyl metabolite is pharmacologically active, the reduced tolterodine blood level does not result in any loss of efficacy with rapid metabolisers. Nevertheless, it is desirable that fluctuations such as these between individuals are avoided and that differences in efficacy which result therefrom are avoided. Moreover, different plasma levels occur if tolterodine is administered with or without the ingestion of food. In principle, these problems can be avoided by the transdermal administration of tolterodine, since the active ingredient is then supplied directly to the blood circulation without passing through the gastro-intestinal tract and the bile duct. The plasma fluctuations comprising high concentration peaks which occur with oral administration, and which result in undesirable side-effects such as dry mouth, dyspepsia, sickness, accommodation problems and confusion, can be avoided by transdermal administration. Similarly, levels of active ingredient which decrease below the threshold of efficacy, and the involuntary, round the clock discharge of urine can be avoided. Furthermore, the liver is subjected to considerably less loading by the active ingredient due to the avoidance of the bile duct, which is especially desirable for patients with a pre-damaged liver, such as patients with cirrhosis of the liver, for example.
WO 98/03067 A1 teaches the use of S-tolterodine for the treatment of bladder voiding disorders, including incontinence. Amongst other methods, transdermal application is also proposed there for the administration of the active ingredient. However, the aforementioned patent contains no technical teaching on the implementation of transdermal application and does not contain an example which relates thereto.